rs35554503

Positions:

chr14-63977907-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000555002.6(SYNE2):c.1296C>A(p.Ser432Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,607,958 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 93 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 93 hom. )

Consequence

SYNE2
ENST00000555002.6 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.706

Variant links:

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SYNE2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018267334).

BP6

Variant 14-63977907-C-A is Benign according to our data. Variant chr14-63977907-C-A is described in ClinVar as [Benign]. Clinvar id is 130469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.1296C>A	p.Ser432Arg	missense_variant, splice_region_variant	13/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.1296C>A	p.Ser432Arg	missense_variant, splice_region_variant	13/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2811

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0645

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00464

AC:

1156

AN:

249250

Hom.:

AF XY:

0.00355

AC XY:

480

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.0660

Gnomad AMR exome

AF:

0.00322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00191

AC:

2775

AN:

1455828

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1189

AN XY:

724654

show subpopulations

Gnomad4 AFR exome

AF:

0.0655

Gnomad4 AMR exome

AF:

0.00396

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000949

Gnomad4 OTH exome

AF:

0.00462

GnomAD4 genome

AF:

0.0186

AC:

2823

AN:

152130

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1319

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0646

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00464

Hom.:

Bravo

AF:

0.0219

ESP6500AA

AF:

0.0600

AC:

223

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00573

AC:

692

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 08, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.033

.;T;T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.68

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;L;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.051

T;.;T;T

Sift4G

Uncertain

0.050

T;D;T;D

Polyphen

0.012

B;.;B;.

Vest4

0.29

MutPred

0.13

Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);

MVP

0.36

MPC

0.052

ClinPred

0.0076

GERP RS

4.7

Varity_R

0.10

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over